In response to non.5: Glial cells in Aging and Neurodegeneration. It is estimated that one-fifth of the United States population will be 65 and older by the year 2030 (1). The elderly spend millions of dollars each year to treat symptoms accompanying gastrointestinal-related disorders, however, very little is known concerning the etiology of dysfunction. It has been suggested that the dysfunction may be related to changes in local enteric pathways regulating gut function. What is the effect of aging on the enteric nervous system (ENS) and how do these changes influence gastrointestinal function? Several studies have shown a gradual degeneration of enteric neurons with age. Recent results from our laboratory suggest that the degeneration may be due in part to alterations in glial cell/neural interactions in enteric ganglia. Hence, the aim of the proposed study is to investigate the hypothesis that a deficit in glial cell derived neurotrophic factor (GDNF) activity in the ENS activates neurodegenerative processes within the aging gut. More specifically, studies are designed to determined whether 1) there is reduced sensitivity of enteric neurons to GDNF as a result of a down regulation of neural GDNF receptors and 2) an age-related decrease in the GDNF synthesis by glial cells. We will employ a multifaceted approach to examine the effect of GDNF deficiency on enteric neural function. Electrophysiological measurements of neurally evoked ion transport will be used to assess function. Immunohistochemical techniques will be used to examine changes in vasoactive intestinal polypeptide (VIP)-, nitric oxide synthase (NOS)- and acetylcholine containing neurons. Finally, western blot analysis will be employed to monitor changes in GDNF and GDNFa receptor levels. GDNFa receptor gene transfer and exogenous GDNF will be administered to partially restore neural activity in our aging models. This study is novel and important. It will provide the first line of evidence demonstrating a link between abnormal glial cell function and enteric neurodegeneration in the aging gut.